Genetic Variant NM_032387.5:c.1691A>C (chr17-42787492-A-C) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_032387.5(WNK4):c.1691A>C(p.Asp564Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000777 in 1,286,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D564H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.8e-7 ( 0 hom. )

Consequence

WNK4
NM_032387.5 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1O:1

Conservation

PhyloP100: 8.92

Publications

16 publications found

Variant links:

Genes affected

WNK4 (HGNC:14544): (WNK lysine deficient protein kinase 4) This gene encodes a member of the WNK family of serine-threonine protein kinases. The kinase is part of the tight junction complex in kidney cells, and regulates the balance between NaCl reabsorption and K(+) secretion. The kinase regulates the activities of several types of ion channels, cotransporters, and exchangers involved in electrolyte flux in epithelial cells. Mutations in this gene result in pseudohypoaldosteronism type IIB.[provided by RefSeq, Sep 2009]

WNK4 Gene-Disease associations (from GenCC):

pseudohypoaldosteronism type 2B
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

WNK4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_032387.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.868

PP5

Variant 17-42787492-A-C is Pathogenic according to our data. Variant chr17-42787492-A-C is described in ClinVar as Pathogenic. ClinVar VariationId is 7662.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
WNK4	NM_032387.5 link	c.1691A>C	p.Asp564Ala	missense_variant	Exon 7 of 19	ENST00000246914.10	NP_115763.2	Q96J92-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
WNK4	ENST00000246914.10 link	c.1691A>C	p.Asp564Ala	missense_variant	Exon 7 of 19	1	NM_032387.5	ENSP00000246914.4		Q96J92-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.77e-7

AC:

AN:

1286518

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

638574

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30014

American (AMR)

AF:

0.00

AC:

AN:

39450

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19328

East Asian (EAS)

AF:

0.00

AC:

AN:

24586

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84870

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4844

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

998186

Other (OTH)

AF:

0.00

AC:

AN:

48846

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Pseudohypoaldosteronism type 2B

Pathogenic:1Other:1

Aug 10, 2001

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.72

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.95

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.87

MetaSVM

Uncertain

0.33

MutationAssessor

Uncertain

2.9

PhyloP100

8.9

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-7.7

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0090

Polyphen

1.0

Vest4

0.85

MutPred

0.58

Loss of catalytic residue at D564 (P = 0.2436);

MVP

0.91

MPC

0.21

ClinPred

1.0

GERP RS

5.0

Varity_R

0.94

gMVP

0.67

Mutation Taster

=13/87

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over